Germline mutations in BRCA1 confer a high risk of breast and ovarian cancers to female carriers. However, the age of onset of breast cancer can vary substantially, even between individuals in the same family. Currently several lines of evidence suggest that other genes modify the breast and ovarian cancer risk conferred by BRCA1 mutations. The variability in age of onset of breast cancer and estimated lifetime risk of breast cancer for BRCA1 mutation carriers depending on the population of ascertainment were the first pieces of suggestive evidence. Secondly, there is accumulating evidence that familial breast cancer risk is not entirely accounted for by mutations in BRCA1 and BRCA2. Finally, there is preliminary data from several association studies, looking at HRAS, APC, the androgen receptor, AIB1, hRad51 and NAT2, which demonstrate that certain alleles of these genes modify penetrance in BRCA1 mutation carriers. All of these various lines of evidence clearly suggest, and we hypothesize, that other genetic factors in addition to mutation status influence cancer risk in BRCA1 and BRCA2 mutation carriers. This proposal seeks to identify genes which modify breast cancer penetrance in BRCA1 mutation carriers. We currently have samples from 109 families with BRCA1 mutations; this sample set will be enlarged in the first part of the study. Two approaches will be utilized to study modifiers of BRCA1 penetrance; first we will examine candidate genes from DNA repair pathways for any association with breast cancer phenotype and secondly we will conduct a genome wide search to look for genomic regions that may contain novel genes. This proposal outlines a five year training program which will allow the candidate to the skills and experience required of an independent physician-scientist. The educational program will combine training in genetic epidemiology and hands-on laboratory experience to provide a broad knowledge base. The research proposal will enable the candidate to transition into an independent investigator capable of integrating mutation analysis, genotyping, statistical genetics and clinical diagnosis in future studies of the molecular basis of the genetics of cancer.